SAMUEL A. DEADWYLER - Primate Testing - 2007

Abstract: DESCRIPTION (provided by applicant): The purpose of
this research project is to assess the manner in which information
processing in brain structures of nonhuman primates is re-organized by
the introduction of and sustained exposure to cocaine as a reinforcer
for complex cognitive tasks. It has long been implicitly assumed in
analyses of human drug addiction that substances which are abused
somehow take over normal reinforcement mechanisms in the brain,
diverting such "reward pathways" to the control of drug seeking
activities. Using a well-characterized short-term memory/executive
function paradigm (multi-object delayed match to sample [DMS] task)
studies will determine how cognitive processing is affected by acute and
longterm exposure to cocaine as a reinforcer in this task. This primate
model of cognitive function has been characterized in recent PET imaging
and electrophysiological recording studies from this laboratory. On the
basis of that work three important brain regions, medial temporal lobe (MTL),
dorsal prefrontal cortex (DPFC) and the dorsal and ventral striatum (D/VStr),
shown to be engaged during task performance, will be assessed for
effects of cocaine on cognitive processing. Aim 1 will determine
neuronal firing characteristics in these three brain regions associated
with performance of the DMS task and will identify single neuron
correlates of low vs. high cognitive load trials. Aim 2 will examine how
these neural correlates change when the task is performed for cocaine
injections delivered as the trial reinforcer in comparison to normal
appetitive (juice) rewards. Aim 3 will extend the above analyses to
animals that are repeatedly exposed to conditions in which cocaine and
juice reinforcers are implemented in the same random manner during
day-to-day testing for a period of six months in order to assess
cumulative changes in DMS responding and associated neuronal correlates
over a time period in which performance is sustained at criterion levels
by both reinforcers. The final Aim 4 will assess the effects of stress
on cocaine vs. juice reinforced DMS performance and associated neural
correlates of cognitive load (Aim 1), induced by a method of sleep
deprivation perfected for nonhuman primates in this laboratory.
Relevance: In a society that is evolving more and more toward increased
stress and demand on its citizens the individual level of cocaine abuse
is a major health care problem. Such behavior eventually results in
inability of the addict to cope with the complex nuances of a complex
technologically-based work place. Turning to drugs is a natural course
of action for pressured, overworked and under employed personnel.How
cocaine use advances to addiction in this context is directly related to
effects on cognition, reasoning and decision making. Therefore
understanding how cocaine modulates and gradually over time eliminates
effective cognitive processing, as studied here, is of primary
importance in the prevention of drug addiction.

Public Health Relevance: This Public Health Relevance is not available.

Subjects. Eight adult male rhesus monkeys (Macaca mulatta) weighing (8.0–11.0
kg) were used in this study. They were individually housed in stainless
steel cages in temperature and humidity controlled colony rooms with
lighting maintained on a 6:00 A.M/6:00 P.M. on/off schedule and fed a
diet of monkey chow supplemented by fresh fruit to maintain daily
monitored body weight. Fluid intake was restricted in time and amount
such that a prescribed volume of an animal's normal daily fluid intake
(80 ml/kg) was received either during the behavioral testing session, or
within 2 h of being returned to the home cage.

Behavioral Testing.
Each monkey was exposed to six different testing conditions [Normal
Vehicle, Alert orexin-A (i.v. and nasal), Sleep Deprivation, Sleep
Deprivation + orexin-A (i.v. or nasal)], which required 11–14 test
sessions for each of the eight monkeys. Animals were placed in a primate
chair 1.5 m in front of an LCD-front-projection screen for daily testing
on a multi-image visual delayed match-to-sample (DMS) task and performed
150–300 trials per session (Hampson et al., 2004; Porrino et al., 2005).
Animals were trained to move a cursor tracked by a fluorescent marker
attached to the back of the monkey's hand into the images by positioning
the hand within a two dimensional coordinate system on the chair
counter. Stimuli consisted of clip art images projected as 25 cm squares
within a 3 x 3 position matrix onto a 1.0 x 1.0 m display. All images
were unique to a particular trial during a session and no image was
exposed on more than on one trial per session. Responses to appropriate
stimuli were rewarded with diluted fruit juice delivered via a sipper
tube placed in front of the mouth. All animals were trained to a stable
baseline on the DMS task in which delay varied randomly from 1 to 90 s
on a given trial, and the number of non-match stimuli (images) varied
randomly from 1 to 7 in the Match phase of the task. As shown previously
performance accuracy varied directly with duration of delay and number
of non-match images (#images) presented in the Match phase (Hampson et
al., 2004; Porrino et al., 2005). Sets of stimulus images were routinely
changed every 2 weeks to maintain the trial-unique feature of each
session. Animals performed the task on consecutive days each week.

Sleep Deprivation Procedure.
Sleep deprivation consisted of 30–36 h of continuous sleep prevention
and wakefulness supervised continuously by laboratory personnel as
previously verified using EEG recordings of sleep architecture. On sleep
deprivation nights animals were maintained in a cage separate from their
home cage in a continuously lighted room and kept awake with videos,
music, occasional treats, gentle cage shaking, and interaction with
technicians (working in 3 h shifts) through the night, until the usual
daily testing time the next day. After testing animals were returned to
their home cage and allowed to sleep. In a previous investigation (Porrino
et al., 2005) evidence was provided that changes in brain imaging
correlates of local glucose utilization during the DMS task (see below)
were consistent with simultaneously recorded EEG changes produced by
30–36 h of sleep deprivation. Hence, replication of the same brain
imaging correlates of sleep deprivation in this study verified that each
animal was tested in the same sleep loss condition as reported
preciously. Intervals of 10 d, mandated by IACUC regulations, were
interspersed between sleep deprivation episodes for each animal. There
were no residual effects of the 30–36 h sleep deprivation regimen on
testing 24 h afterward at which time animals had returned to their
normal sleep patterns.

Please email: SAMUEL A. DEADWYLER,
sdeadwyl@wfubmc.edu to protest the inhumane use of animals in this
experiment. We would also love to know about your efforts with this
cause:
saen@saenonline.org

Rats, mice, birds, amphibians and other animals have
been excluded from coverage by the Animal Welfare Act. Therefore research
facility reports do not include these animals. As a result of this
situation, a blank report, or one with few animals listed, does not mean
that a facility has not performed experiments on non-reportable animals. A
blank form does mean that the facility in question has not used covered
animals (primates, dogs, cats, rabbits, guinea pigs, hamsters, pigs,
sheep, goats, etc.). Rats and mice alone are believed to comprise over 90%
of the animals used in experimentation. Therefore the majority of animals
used at research facilities are not even counted.